1.
Carl Ferdinand Cori
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In 2004 both were designated a National Historic Chemical Landmark in recognition of their work that elucidated carbohydrate metabolism. Carl was the son of Carl Isidor Cori, a zoologist, and Maria née Lippich, the Cori Family came from the Papal State to the Royal Bohemian Crownland, Austrian Circle at the end of the 17th century. Carl Ferdinands grandfather Eduard Cori was an officer and beekeeper in Brüx. Carl Ferdinands younger sister Margarete Cori was a lecturer of Prague and he grew up in Trieste, where his father Carl Isidor was the director of the Marine Biological Station. In late 1914 the Cori family moved to Prague and Carl entered the school of Charles University in Prague. While studying there he met Gerty Theresa Radnitz and he was drafted into the Austro-Hungarian Army and served in the ski corps, and later was transferred to the sanitary corps, for which he set up a laboratory in Trieste. At the end of the war Carl completed his studies, graduating with Gerty in 1920, Carl and Gerty married that year and worked together in clinics in Vienna. Carl was invited to Graz to work with Otto Loewi to study the effect of the vagus nerve on the heart, while Carl was in Graz, Gerty remained in Vienna. A year later Carl was offered a position at the State Institute for the Study of Malignant Diseases in Buffalo, New York, in 1928, they became naturalized citizens of the United States. While at the Institute the Coris’ research focused on carbohydrate metabolism, in 1931 Carl accepted a position at the Washington University School of Medicine in St. Louis, Missouri. Carl joined as professor of pharmacology and in 1942 was made professor of biochemistry, in St. Louis, the Coris continued their research on glycogen and glucose and began to describe glycogenolysis, identifying and synthesizing the important enzyme glycogen phosphorylase. For these discoveries, they received the Nobel Prize in Physiology or Medicine in 1947, Gerty died in 1957 and Carl married Anne Fitz-Gerald Jones in 1960. He stayed on at Washington University until 1966, when he retired as chair of the biochemistry department and he was appointed visiting professor of Biological Chemistry at Harvard University while maintaining a laboratory space at the Massachusetts General Hospital, where he pursued research in genetics. From 1968 to 1983 he collaborated with noted geneticist Salomé Glüecksohn-Waelsch of the Albert Einstein College of Medicine in New York, in 1976 Carl received the Laurea honoris causa in Medicine from the University of Trieste. Cori was elected a Foreign Member of the Royal Society in 1950 and the Carl Cori Endowed Professorship at Washington University is named in his honor, currently held by Colin Nichols
2.
Gerty Cori
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Gerty was not a nickname, but rather she was named after an Austrian warship. Because of deteriorating conditions in Europe, the couple emigrated to the United States in 1922, Gerty Cori continued her early interest in medical research, collaborating in the laboratory with Carl. She published research findings coauthored with her husband, as well as publishing singly, unlike her husband, she had difficulty securing research positions, and the ones she obtained provided meager pay. Her husband insisted on continuing their collaboration, though he was discouraged from doing so by the institutions that employed him and they also identified the important catalyzing compound, the Cori ester. In 2004, both Gerty and Carl Cori were designated a National Historic Chemical Landmark in recognition of their work in clarifying carbohydrate metabolism, in 1957, Gerty Cori died after a ten-year struggle with myelosclerosis. She remained active in the laboratory until the end. She received recognition for her achievements through multiple awards and honors, the Cori crater on the Moon and the Cori crater on Venus are named after her. Gerty Theresa Radnitz was born into a Jewish family in Prague in 1896 and her father, Otto Radnitz, was a chemist who became manager of sugar refineries after inventing a successful method for refining sugar. Her mother, Martha, a friend of Franz Kafka, was a sophisticated woman. Gerty was tutored at home before enrolling in a Lyceum for girls, pursuing the study of science, Gerty learned that she lacked the prerequisites in Latin, physics, chemistry, and mathematics. Over the course of a year, she managed to study the equivalent of eight years of Latin, five years of science and her uncle, a professor of pediatrics, encouraged her to attend medical school, so she studied for and passed the University entrance examination. She was admitted to the school of the Karl-Ferdinands-Universität in Prague in 1914. While studying she met Carl Cori who was attracted to her charm, vitality, sense of humor and her love of the outdoors. Gerty and Carl had both entered medical school at eighteen and both graduated in 1920, Gerty converted to Catholicism, enabling her and Carl to marry in the Roman Catholic Church. They moved to Vienna, Austria, where Gerty spent the two years at the Carolinen Childrens Hospital, and her husband worked in a laboratory. Carl served in the Austrian army during World War I after being drafted, life was difficult following World War I, and Gerty suffered from xerophthalmia caused by severe malnutrition due to food shortages. These problems, in conjunction with the increasing anti-Semitism, contributed to the Coris decision to leave Europe, in 1922, the Coris both immigrated to the United States to pursue medical research at the State Institute for the Study of Malignant Diseases in Buffalo, New York. In 1928, they became naturalized citizens of the United States, the director for the Institute threatened to dismiss Gerty if she did not cease collaborative research with her husband
3.
Lactic acid
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Lactic acid is an organic compound with the formula CH3CHCO2H. In its solid state, it is white and water-soluble, in its liquid state, it is clear. It is produced naturally and synthetically. With a hydroxyl group adjacent to the group, lactic acid is classified as an alpha-hydroxy acid. In the form of its base called lactate, it plays a role in several biochemical processes. In solution, it can ionize a proton from the carboxyl group, compared to acetic acid, its pKa is 1 unit less, meaning lactic acid deprotonates ten times more easily than acetic acid does. This higher acidity is the consequence of the hydrogen bonding between the α-hydroxyl and the carboxylate group. Lactic acid is chiral, consisting of two optical isomers, one is known as L--lactic acid or -lactic acid and the other, its mirror image, is D--lactic acid or -lactic acid. A mixture of the two in equal amounts is called DL-lactic acid, or racemic lactic acid, DL-lactic acid is miscible with water and with ethanol above its melting point which is around 17 or 18 °C. D-lactic acid and L-lactic acid have a melting point. In animals, L-lactate is constantly produced from pyruvate via the enzyme lactate dehydrogenase in a process of fermentation during normal metabolism and exercise. The concentration of lactate is usually 1–2 mmol/L at rest. In industry, lactic acid fermentation is performed by lactic acid bacteria and these bacteria can also grow in the mouth, the acid they produce is responsible for the tooth decay known as caries. In medicine, lactate is one of the components of lactated Ringers solution. These intravenous fluids consist of sodium and potassium cations along with lactate and chloride anions in solution with distilled water and it is most commonly used for fluid resuscitation after blood loss due to trauma, surgery, or burns. Lactic acid was isolated for the first time by the Swedish chemist Carl Wilhelm Scheele in 1780 from sour milk, the name reflects the lact- combining form derived from the Latin word for milk. In 1808, Jöns Jacob Berzelius discovered that lactic acid also is produced in muscles during exertion and its structure was established by Johannes Wislicenus in 1873. In 1856, Louis Pasteur discovered Lactobacillus and its role in the making of lactic acid, lactic acid started to be produced commercially by the German pharmacy Boehringer Ingelheim in 1895
4.
Glycolysis
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Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+. The free energy released in this process is used to form the high-energy molecules ATP, glycolysis is a determined sequence of ten enzyme-catalyzed reactions. The intermediates provide entry points to glycolysis, for example, most monosaccharides, such as fructose and galactose, can be converted to one of these intermediates. The intermediates may also be directly useful, for example, the intermediate dihydroxyacetone phosphate is a source of the glycerol that combines with fatty acids to form fat. Glycolysis is an oxygen independent metabolic pathway, meaning that it not use molecular oxygen for any of its reactions. However the products of glycolysis are sometimes metabolized using atmospheric oxygen, when molecular oxygen is used for the metabolism of the products of glycolysis the process is usually referred to as aerobic, whereas if no oxygen is used the process is said to be anaerobic. Thus, glycolysis occurs, with variations, in all organisms. The wide occurrence of glycolysis indicates that it is one of the most ancient metabolic pathways, glycolysis could thus have originated from chemical constraints of the prebiotic world. Glycolysis occurs in most organisms in the cytosol of the cell, the most common type of glycolysis is the Embden–Meyerhof–Parnas, which was discovered by Gustav Embden, Otto Meyerhof, and Jakub Karol Parnas. Glycolysis also refers to other pathways, such as the Entner–Doudoroff pathway, however, the discussion here will be limited to the Embden–Meyerhof–Parnas pathway. The overall reaction of glycolysis is, The use of symbols in this equation makes it appear unbalanced with respect to oxygen atoms, hydrogen atoms, and charges. In the cellular environment, all three groups of ADP dissociate into −O− and H+, giving ADP3−, and this ion tends to exist in an ionic bond with Mg2+. ATP behaves identically except that it has four groups, giving ATPMg2−. When these differences along with the charges on the two phosphate groups are considered together, the net charges of −4 on each side are balanced. For simple fermentations, the metabolism of one molecule of glucose to two molecules of pyruvate has a net yield of two molecules of ATP, most cells will then carry out further reactions to repay the used NAD+ and produce a final product of ethanol or lactic acid. Many bacteria use inorganic compounds as hydrogen acceptors to regenerate the NAD+, cells performing aerobic respiration synthesize much more ATP, but not as part of glycolysis. These further aerobic reactions use pyruvate and NADH + H+ from glycolysis, the pathway of glycolysis as it is known today took almost 100 years to fully discover. The combined results of many experiments were required in order to understand the pathway as a whole
5.
Nobel Prize in Physiology or Medicine
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The Nobel Prize in Physiology or Medicine, administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the fields of life sciences and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, Nobel was personally interested in experimental physiology and wanted to establish a prize for progress through scientific discoveries in laboratories. The Nobel Prize is presented to the recipient at a ceremony on 10 December, the anniversary of Nobels death, along with a diploma. The front side of the medal provides the profile of Alfred Nobel as depicted on the medals for Physics, Chemistry. As of 2015,106 Nobel Prizes in Physiology or Medicine have been awarded to 198 men and 12 women. The first Nobel Prize in Physiology or Medicine was awarded in 1901 to the German physiologist Emil von Behring, for his work on serum therapy and this includes one to António Egas Moniz in 1949 for the prefrontal leucotomy, bestowed despite protests from the medical establishment. Other controversies resulted from disagreements over who was included in the award, the 1952 prize to Selman Waksman was litigated in court, and half the patent rights awarded to his co-discoverer Albert Schatz who was not recognized by the prize. The 1962 prize awarded to James D, since the Nobel Prize rules forbid nominations of the deceased, longevity is an asset, one prize being awarded as long as 50 years after the discovery. Alfred Nobel was born on 21 October 1833 in Stockholm, Sweden into a family of engineers and he was a chemist, engineer and inventor who amassed a fortune during his lifetime, most of it from his 355 inventions of which dynamite is the most famous. He was interested in experimental physiology and set up his own labs in France, in 1888, Nobel was surprised to read his own obituary, titled The merchant of death is dead, in a French newspaper. Though Nobel wrote several wills during his lifetime, the last was written a little over a year before he died at the age of 63, because his will was contested, it was not approved by the Storting until 26 April 1897. After Nobels death, the Nobel Foundation was set up to manage the assets of the bequest, in 1900, the Nobel Foundations newly created statutes were promulgated by Swedish King Oscar II. According to Nobels will, the Karolinska Institutet in Sweden, a medical school, today, the prize is commonly referred to as the Nobel Prize in Medicine. It was important to Nobel that the prize be awarded for a discovery, per the provisions of the will, only select persons are eligible to nominate individuals for the award. Past Nobel laureates may also nominate, until 1977, all professors of Karolinska Institutet together decided on the Nobel Prize in Physiology or Medicine. Therefore, the Nobel Assembly was constituted, consisting of 50 professors at Karolinska Institutet. It elects the Nobel Committee with 5 members who evaluate the nominees, the Secretary who is in charge of the organization, in 1968, a provision was added that no more than three persons may share a Nobel prize. True to its mandate, the Committee has selected researchers working in the sciences over those who have made applied contributions
6.
Adenosine triphosphate
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Adenosine triphosphate is a nucleotide, also called a nucleoside triphosphate, is a small molecule used in cells as a coenzyme. It is often referred to as the unit of currency of intracellular energy transfer. ATP transports chemical energy within cells for metabolism, most cellular functions need energy in order to be carried out, synthesis of proteins, synthesis of membranes, movement of the cell, cellular division, transport of various solutes etc. The ATP is the molecule that carries energy to the place where the energy is needed, when ATP breaks into ADP and Pi, the breakdown of the last covalent link of phosphate liberates energy that is used in reactions where it is needed. Substrate-level phosphorylation, oxidative phosphorylation in cellular respiration, and photophosphorylation in photosynthesis are three mechanisms of ATP biosynthesis. Metabolic processes that use ATP as an energy source convert it back into its precursors, ATP is therefore continuously recycled in organisms, the human body, which on average contains only 250 grams of ATP, turns over its own body weight equivalent in ATP each day. ATP is used as a substrate in signal transduction pathways by kinases that phosphorylate proteins and it is also used by adenylate cyclase, which uses ATP to produce the second messenger molecule cyclic AMP. The ratio between ATP and AMP is used as a way for a cell to sense how much energy is available and control the metabolic pathways that produce and consume ATP. Apart from its roles in signaling and energy metabolism, ATP is also incorporated into nucleic acids by polymerases in the process of transcription, ATP is the neurotransmitter believed to signal the sense of taste. The structure of this consists of a purine base attached by the 9′ nitrogen atom to the 1′ carbon atom of a pentose sugar. Three phosphate groups are attached at the 5′ carbon atom of the pentose sugar and it is the addition and removal of these phosphate groups that inter-convert ATP, ADP and AMP. When ATP is used in DNA synthesis, the sugar is first converted to deoxyribose by ribonucleotide reductase. ATP was discovered in 1929 by Karl Lohmann, and independently by Cyrus Fiske and Yellapragada Subbarow of Harvard Medical School and it was proposed to be the intermediary molecule between energy-yielding and energy-requiring reactions in cells by Fritz Albert Lipmann in 1941. It was first artificially synthesized by Alexander Todd in 1948, ATP consists of adenosine – composed of an adenine ring and a ribose sugar – and three phosphate groups. The phosphoryl groups, starting with the group closest to the ribose, are referred to as the alpha, beta, consequently, it is closely related to the adenosine nucleotide, a monomer of RNA. ATP is highly soluble in water and is stable in solutions between pH6.8 and 7.4, but is rapidly hydrolysed at extreme pH. Consequently, ATP is best stored as an anhydrous salt, ATP is an unstable molecule in unbuffered water, in which it hydrolyses to ADP and phosphate. This is because the strength of the bonds between the groups in ATP is less than the strength of the hydrogen bonds, between its products, and water
7.
Glycogen
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Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in humans, animals, and fungi. The polysaccharide structure represents the main form of glucose in the body. In humans, glycogen is made and stored primarily in the cells of the liver, glycogen functions as the secondary long-term energy storage, with the primary energy stores being fats held in adipose tissue. Muscle glycogen is converted into glucose by muscle cells, and liver glycogen converts to glucose for use throughout the body including the nervous system. Glycogen is the analogue of starch, a polymer that functions as energy storage in plants. It has a similar to amylopectin, but is more extensively branched. Both are white powders in their dry state, glycogen is found in the form of granules in the cytosol/cytoplasm in many cell types, and plays an important role in the glucose cycle. Glycogen forms a reserve that can be quickly mobilized to meet a sudden need for glucose. In the liver, glycogen can make up from 5–6% of the fresh weight. Only the glycogen stored in the liver can be accessible to other organs. In the muscles, glycogen is found in a low concentration, the amount of glycogen stored in the body—especially within the muscles, liver, and red blood cells—mostly depends on physical training, basal metabolic rate, and eating habits. Small amounts of glycogen are found in the kidneys, and even smaller amounts in certain cells in the brain. The uterus also stores glycogen during pregnancy to nourish the embryo, glycogen is a branched biopolymer consisting of linear chains of glucose residues with further chains branching off every 8 to 12 glucoses or so. Glucoses are linked together linearly by α glycosidic bonds from one glucose to the next, branches are linked to the chains from which they are branching off by α glycosidic bonds between the first glucose of the new branch and a glucose on the stem chain. Due to the way glycogen is synthesised, every glycogen granule has at its core a glycogenin protein. Glycogen in muscle, liver, and fat cells is stored in a hydrated form, as a meal containing carbohydrates or protein is eaten and digested, blood glucose levels rise, and the pancreas secretes insulin. Blood glucose from the vein enters liver cells. Insulin acts on the hepatocytes to stimulate the action of several enzymes, glucose molecules are added to the chains of glycogen as long as both insulin and glucose remain plentiful
8.
Skeletal muscle
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Skeletal muscle is one of three major muscle types, the others being cardiac muscle and smooth muscle. It is a form of striated muscle tissue which is under the control of the somatic nervous system. Most skeletal muscles are attached to bones by bundles of collagen fibers known as tendons, a skeletal muscle refers to multiple bundles of cells called muscle fibers. The fibres and muscles are surrounded by connective tissue layers called fasciae, Muscle fibres, or muscle cells, are formed from the fusion of developmental myoblasts in a process known as myogenesis. Muscle fibres are cylindrical, and have more than one nucleus, Muscle fibers are in turn composed of myofibrils. The myofibrils are composed of actin and myosin filaments, repeated in units called sarcomeres, the sarcomere is responsible for the striated appearance of skeletal muscle, and forms the basic machinery necessary for muscle contraction. Connective tissue is present in all muscles as fascia, Muscle fibres are the individual contractile units within muscle. A single muscle such as the biceps contains many muscle fibres, another group of cells, the myosatellite cells are found between the basement membrane and the sarcolemma of muscle fibers. These cells are normally quiescent but can be activated by exercise or pathology to provide additional myonuclei for muscle growth or repair, development Individual muscle fibers are formed during development from the fusion of several undifferentiated immature cells known as myoblasts into long, cylindrical, multi-nucleated cells. Differentiation into this state is completed before birth with the cells continuing to grow in size thereafter. Microanatomy Skeletal muscle exhibits a distinctive banding pattern when viewed under the due to the arrangement of cytoskeletal elements in the cytoplasm of the muscle fibers. The principal cytoplasmic proteins are myosin and actin which are arranged in a unit called a sarcomere. The interaction of myosin and actin is responsible for muscle contraction, every single organelle and macromolecule of a muscle fiber is arranged to ensure form meets function. The cell membrane is called the sarcolemma with the known as the sarcoplasm. In the sarcoplasm are the myofibrils, the myofibrils are long protein bundles about 1 micrometer in diameter each containing myofilaments. Pressed against the inside of the sarcolemma are the unusual flattened myonuclei, between the myofibrils are the mitochondria. While the muscle fiber does not have a smooth endoplasmic reticulum, the sarcoplasmic reticulum surrounds the myofibrils and holds a reserve of the calcium ions needed to cause a muscle contraction. Periodically, it has dilated end sacs known as terminal cisternae and these cross the muscle fiber from one side to the other
9.
Glycogenolysis
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Glycogenolysis is the breakdown of glycogen to glucose-6-phosphate and glycogen. Glycogen branches are catabolized by the removal of glucose monomers via phosphorolysis. Glucose-1-phosphate is converted to glucose-6-phosphate by the enzyme phosphoglucomutase, glucose residues are phosphorolysed from branches of glycogen until four residues before a glucose that is branched with a α linkage. Glycogen debranching enzyme then transfers three of the remaining four units to the end of another glycogen branch. This exposes the α branching point, which is hydrolysed by α glucosidase, removing the final glucose residue of the branch as a molecule of glucose and this is the only case in which a glycogen metabolite is not glucose-1-phosphate. The glucose is subsequently phosphorylated to glucose-6-phosphate by hexokinase, Glycogenolysis takes place in the cells of the muscle and liver tissues in response to hormonal and neural signals. In particular, glycogenolysis plays an important role in the fight-or-flight response, in myocytes, glycogen degradation serves to provide an immediate source of glucose-6-phosphate for glycolysis, to provide energy for muscle contraction. In hepatocytes, the purpose of the breakdown of glycogen is for the release of glucose into the bloodstream for uptake by other cells. Glycogenolysis is regulated hormonally in response to blood sugar levels by glucagon and insulin, in myocytes, glycogen degradation may also be stimulated by neural signals. Parenteral administration of glucagon is a human medical intervention in diabetic emergencies when sugar cannot be given orally. It can also be administered intramuscularly, mutations at the liver enzyme glycogen phosphorylase lead to glycogen storage disease VI. Mutations at the enzyme glycogen phosphorylase lead to McArdles disease. Deficiencies at the glycogen debranching enzyme lead to glycogen storage disease III, glycogenesis The chemical logic of glycogen degradation at ufp. pt Glycogenolysis at the US National Library of Medicine Medical Subject Headings
10.
Myocyte
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Skeletal muscle is one of three major muscle types, the others being cardiac muscle and smooth muscle. It is a form of striated muscle tissue which is under the control of the somatic nervous system. Most skeletal muscles are attached to bones by bundles of collagen fibers known as tendons, a skeletal muscle refers to multiple bundles of cells called muscle fibers. The fibres and muscles are surrounded by connective tissue layers called fasciae, Muscle fibres, or muscle cells, are formed from the fusion of developmental myoblasts in a process known as myogenesis. Muscle fibres are cylindrical, and have more than one nucleus, Muscle fibers are in turn composed of myofibrils. The myofibrils are composed of actin and myosin filaments, repeated in units called sarcomeres, the sarcomere is responsible for the striated appearance of skeletal muscle, and forms the basic machinery necessary for muscle contraction. Connective tissue is present in all muscles as fascia, Muscle fibres are the individual contractile units within muscle. A single muscle such as the biceps contains many muscle fibres, another group of cells, the myosatellite cells are found between the basement membrane and the sarcolemma of muscle fibers. These cells are normally quiescent but can be activated by exercise or pathology to provide additional myonuclei for muscle growth or repair, development Individual muscle fibers are formed during development from the fusion of several undifferentiated immature cells known as myoblasts into long, cylindrical, multi-nucleated cells. Differentiation into this state is completed before birth with the cells continuing to grow in size thereafter. Microanatomy Skeletal muscle exhibits a distinctive banding pattern when viewed under the due to the arrangement of cytoskeletal elements in the cytoplasm of the muscle fibers. The principal cytoplasmic proteins are myosin and actin which are arranged in a unit called a sarcomere. The interaction of myosin and actin is responsible for muscle contraction, every single organelle and macromolecule of a muscle fiber is arranged to ensure form meets function. The cell membrane is called the sarcolemma with the known as the sarcoplasm. In the sarcoplasm are the myofibrils, the myofibrils are long protein bundles about 1 micrometer in diameter each containing myofilaments. Pressed against the inside of the sarcolemma are the unusual flattened myonuclei, between the myofibrils are the mitochondria. While the muscle fiber does not have a smooth endoplasmic reticulum, the sarcoplasmic reticulum surrounds the myofibrils and holds a reserve of the calcium ions needed to cause a muscle contraction. Periodically, it has dilated end sacs known as terminal cisternae and these cross the muscle fiber from one side to the other
11.
Pyruvate
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Pyruvic acid is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the base, CH3COCOO−, is a key intermediate in several metabolic pathways. Pyruvic acid can be made from glucose through glycolysis, converted back to carbohydrates via gluconeogenesis and it can also be used to construct the amino acid alanine and can be converted into ethanol or lactic acid via fermentation. Pyruvic acid supplies energy to cells through the citric acid cycle when oxygen is present, pyruvic acid is a colorless liquid with a smell similar to that of acetic acid and is miscible with water. It is the output of the metabolism of known as glycolysis. One molecule of glucose breaks down into two molecules of pyruvate, which are used to provide further energy, in one of two ways. Pyruvate is converted into acetyl-coenzyme A, which is the input for a series of reactions known as the Krebs cycle. Pyruvate is also converted to oxaloacetate by an reaction, which replenishes Krebs cycle intermediates, also. These reactions are named after Hans Adolf Krebs, the biochemist awarded the 1953 Nobel Prize for physiology, jointly with Fritz Lipmann, for research into metabolic processes. The cycle is known as the citric acid cycle or tricarboxylic acid cycle. If insufficient oxygen is available, the acid is broken down anaerobically, creating lactate in animals and ethanol in plants, Pyruvate is a key intersection in the network of metabolic pathways. Pyruvate can be converted into carbohydrates via gluconeogenesis, to fatty acids or energy through acetyl-CoA, to the amino acid alanine, therefore, it unites several key metabolic processes. In glycolysis, phosphoenolpyruvate is converted to pyruvate by pyruvate kinase and this reaction is strongly exergonic and irreversible, in gluconeogenesis, it takes two enzymes, pyruvate carboxylase and PEP carboxykinase, to catalyze the reverse transformation of pyruvate to PEP. Compound C00074 at KEGG Pathway Database, enzyme 2.7.1.40 at KEGG Pathway Database. Compound C00022 at KEGG Pathway Database, click on genes, proteins and metabolites below to link to respective articles. Pyruvate decarboxylation by the pyruvate dehydrogenase complex produces acetyl-CoA, carboxylation by pyruvate carboxylase produces oxaloacetate. Transamination by alanine transaminase produces alanine, reduction by lactate dehydrogenase produces lactate. Pyruvate is sold as a supplement, though evidence supporting this use is lacking
12.
Citric acid cycle
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Its central importance to many biochemical pathways suggests that it was one of the earliest established components of cellular metabolism and may have originated abiogenically. The name of this pathway is derived from citric acid that is consumed. In addition, the cycle consumes acetate and water, reduces NAD+ to NADH, the NADH generated by the TCA cycle is fed into the oxidative phosphorylation pathway. The net result of two closely linked pathways is the oxidation of nutrients to produce usable chemical energy in the form of ATP. In eukaryotic cells, the citric acid cycle occurs in the matrix of the mitochondrion, components of the TCA cycle were derived from anaerobic bacteria, and the TCA cycle itself may have evolved more than once. Theoretically there are alternatives to the TCA cycle, however. If several TCA alternatives had evolved independently, they all appear to have converged to the TCA cycle, the citric acid cycle is a key metabolic pathway that connects carbohydrate, fat, and protein metabolism. The reactions of the cycle are carried out by 8 enzymes that completely oxidize acetate, in the form of acetyl-CoA, through catabolism of sugars, fats, and proteins, the two-carbon organic product acetyl-CoA is produced which enters the citric acid cycle. The NADH and FADH2 generated by the citric acid cycle are in used by the oxidative phosphorylation pathway to generate energy-rich adenosine triphosphate. Acetyl-CoA may also be obtained from the oxidation of fatty acids, the citrate then goes through a series of chemical transformations, losing two carboxyl groups as CO2. The carbons lost as CO2 originate from what was oxaloacetate, not directly from acetyl-CoA, the carbons donated by acetyl-CoA become part of the oxaloacetate carbon backbone after the first turn of the citric acid cycle. Loss of the acetyl-CoA-donated carbons as CO2 requires several turns of the citric acid cycle. However, because of the role of the citric acid cycle in anabolism, they not be lost. Most of the energy available by the oxidative steps of the cycle is transferred as energy-rich electrons to NAD+. For each acetyl group that enters the citric cycle, three molecules of NADH are produced. Electrons are also transferred to the electron acceptor Q, forming QH2, at the end of each cycle, the four-carbon oxaloacetate has been regenerated, and the cycle continues. Two carbon atoms are oxidized to CO2, the energy from these reactions is transferred to other processes through GTP. The NADH generated in the TCA cycle may later be oxidized to drive ATP synthesis in a type of process called oxidative phosphorylation, FADH2 is covalently attached to succinate dehydrogenase, an enzyme which functions both in the CAC and the mitochondrial electron transport chain in oxidative phosphorylation
13.
Anaerobic metabolism
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Fermentation is a metabolic process that converts sugar to acids, gases, or alcohol. It occurs in yeast and bacteria, and also in oxygen-starved muscle cells, Fermentation is also used more broadly to refer to the bulk growth of microorganisms on a growth medium, often with the goal of producing a specific chemical product. French microbiologist Louis Pasteur is often remembered for his insights into fermentation, the science of fermentation is known as zymology. Fermentation takes place when the transport chain is unusable. In this case it becomes the primary means of ATP production. Fermentation turns NADH and pyruvate produced in glycolysis into NAD+. In the presence of O2, NADH and pyruvate are used to generate ATP in respiration and this is called oxidative phosphorylation, and it generates much more ATP than glycolysis alone. For that reason, cells generally benefit from avoiding fermentation when oxygen is available, the exception being obligate anaerobes which cannot tolerate oxygen. The first step, glycolysis, is common to all fermentation pathways, two ADP molecules and two Pi are converted to two ATP and two water molecules via substrate-level phosphorylation. Two molecules of NAD+ are also reduced to NADH, in oxidative phosphorylation the energy for ATP formation is derived from an electrochemical proton gradient generated across the inner mitochondrial membrane via the electron transport chain. Humans have used fermentation to produce drinks and beverages since the Neolithic age, Fermentation can even occur within the stomachs of animals, such as humans. To many people, fermentation simply means the production of alcohol, grains and fruits are fermented to produce beer, if a food soured, one might say it was off or fermented. Here are some definitions of fermentation and they range from informal, general usage to more scientific definitions. Preservation methods for food via microorganisms, any process that produces alcoholic beverages or acidic dairy products. Any large-scale microbial process occurring with or without air, any energy-releasing metabolic process that takes place only under anaerobic conditions. Fermentation does not necessarily have to be carried out in an anaerobic environment, for example, even in the presence of abundant oxygen, yeast cells greatly prefer fermentation to aerobic respiration, as long as sugars are readily available for consumption. The antibiotic activity of hops also inhibits aerobic metabolism in yeast, Fermentation reacts NADH with an endogenous, organic electron acceptor. Usually this is formed from the sugar during the glycolysis step. Sugars are the most common substrate of fermentation, and typical examples of products are ethanol, lactic acid, carbon dioxide
14.
Lactic acid fermentation
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Lactic acid fermentation is a metabolic process by which glucose and other six-carbon sugars are converted into cellular energy and the metabolite lactate. It is a fermentation reaction that occurs in some bacteria and animal cells. Sometimes even when oxygen is present and aerobic metabolism is happening in the mitochondria, if pyruvate is building up faster than it can be metabolized, lactate dehydrogenase catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+. In homolactic fermentation, one molecule of glucose is converted to two molecules of lactic acid. Heterolactic fermentation, in contrast, yields carbon dioxide and ethanol in addition to lactic acid, lactic acid fermentation is used in many areas of the world to produce foods that cannot be produced through other methods. The most commercially important genus of lactic acid-fermenting bacteria is Lactobacillus, though other bacteria, two of the most common applications of lactic acid fermentation are in the production of yogurt and sauerkraut. Kimchi also uses lactic acid fermentation, lactic acid fermentation is also used in the production of sauerkraut. The main type of bacteria used in the production of sauerkraut is of the genus Leuconostoc, as in yogurt, when the acidity rises due to lactic acid-fermenting organisms, many other pathogenic microorganisms are killed. The bacteria produce acid, as well as simple alcohols. These may then combine to form esters, contributing to the flavor of sauerkraut. Lactic acid is a component in the production of sour beers, including Lambics, the main method of producing yogurt is through the lactic acid fermentation of milk with harmless bacteria. The primary bacteria used are typically Lactobacillus bulgaricus and Streptococcus thermophilus and these bacteria produce lactic acid in the milk culture, decreasing its pH and causing it to congeal. The bacteria also produce compounds that give yogurt its distinctive flavor, an additional effect of the lowered pH is the incompatibility of the acidic environment with many other types of harmful bacteria. For a probiotic yogurt, additional types of such as Lactobacillus acidophilus are also added to the culture. Lactobacillus fermentation and accompanying production of acid provides a protective vaginal microbiome that protects against the proliferation of pathogenic organisms
15.
Lactate dehydrogenase
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Lactate dehydrogenase is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvic acid and back, as it converts NAD+ to NADH, a dehydrogenase is an enzyme that transfers a hydride from one molecule to another. LDH exist in four distinct enzyme classes and this article is specifically about the NAD-dependent L-lactate dehydrogenase. Other LDHs act on D-lactate and/or are dependent on cytochrome c, D-lactate dehydrogenase ), LDH is expressed extensively in body tissues, such as blood cells and heart muscle. Because it is released during tissue damage, it is a marker of common injuries, Lactate dehydrogenase catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+. It converts pyruvate, the product of glycolysis, to lactate when oxygen is absent or in short supply. At high concentrations of lactate, the enzyme exhibits feedback inhibition, and it also catalyzes the dehydrogenation of 2-Hydroxybutyrate, but it is a much poorer substrate than lactate. LDH in humans uses His as the acceptor, and works in unison with the coenzyme. The His active site, is not only found in the form of LDH. The noticeable difference between the two subunits that make up LDHs tertiary structure is the replacement of alanine with a glutamine, Lactate dehydrogenase is composed of four subunits. The two most common subunits are the LDH-M and LDH-H protein, encoded by the LDHA and LDHB genes and these two subunits can form five possible tetramers, 4H, 4M, and the three mixed tetramers. LDH-1 —in the heart and in RBC, as well as the brain, LDH-2 —in the reticuloendothelial system LDH-3 —in the lungs LDH-4 —in the kidneys, placenta, and pancreas LDH-5 —in the liver and striated muscle Usually LDH-2 is the predominant form in the serum. A LDH-1 level higher than the LDH-2 level suggests myocardial infarction, the use of this phenomenon to diagnose infarction has been largely superseded by the use of Troponin I or T measurement. There are two more mammalian LDH subunits that can be included in LDH tetramers, LDHC and LDHBx, LDHC is a testes-specific LDH protein, that is encoded by the LDHC gene. LDHBx is a peroxisome-specific LDH protein, LDHBx is the readthrough-form of LDHB. LDHBx is generated by translation of the LDHB mRNA, but the stop codon is interpreted as an amino acid-encoding codon, in consequence, translation continues to the next stop codon. This leads to the addition of seven amino acids to the normal LDH-H protein. The extension contains a peroxisomal targeting signal, so that LDHBx is imported into the peroxisome, the family also contains L-lactate dehydrogenases that catalyse the conversion of L-lactate to pyruvate, the last step in anaerobic glycolysis
16.
Nicotinamide adenine dinucleotide
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Nicotinamide adenine dinucleotide is a coenzyme found in all living cells. The compound is a dinucleotide, because it consists of two nucleotides joined through their phosphate groups, one nucleotide contains an adenine base and the other nicotinamide. Nicotinamide adenine dinucleotide exists in two forms, an oxidized and reduced form abbreviated as NAD+ and NADH respectively, in metabolism, nicotinamide adenine dinucleotide is involved in redox reactions, carrying electrons from one reaction to another. The coenzyme is, therefore, found in two forms in cells, NAD+ is an oxidizing agent – it accepts electrons from other molecules and becomes reduced and this reaction forms NADH, which can then be used as a reducing agent to donate electrons. These electron transfer reactions are the function of NAD. However, it is used in other cellular processes, the most notable one being a substrate of enzymes that add or remove chemical groups from proteins. Because of the importance of these functions, the involved in NAD metabolism are targets for drug discovery. In organisms, NAD can be synthesized from simple building-blocks from the amino acids tryptophan or aspartic acid, in an alternative fashion, more complex components of the coenzymes are taken up from food as the vitamin called niacin. Similar compounds are released by reactions that break down the structure of NAD and these preformed components then pass through a salvage pathway that recycles them back into the active form. Some NAD is also converted into nicotinamide adenine dinucleotide phosphate, the chemistry of this related coenzyme is similar to that of NAD, nicotinamide adenine dinucleotide, like all dinucleotides, consists of two nucleosides joined by a pair of bridging phosphate groups. The nucleosides each contain a ring, one with adenine attached to the first carbon atom. The nicotinamide moiety can be attached in two orientations to this carbon atom. Because of these two structures, the compound exists as two diastereomers. It is the diastereomer of NAD+ that is found in organisms. These nucleotides are joined together by a bridge of two groups through the 5 carbons. In metabolism, the compound accepts or donates electrons in redox reactions, such reactions involve the removal of two hydrogen atoms from the reactant, in the form of a hydride ion, and a proton. The proton is released into solution, while the reductant RH2 is oxidized, the midpoint potential of the NAD+/NADH redox pair is −0.32 volts, which makes NADH a strong reducing agent. The reaction is reversible, when NADH reduces another molecule and is re-oxidized to NAD+
17.
Fermentation
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Fermentation is a metabolic process that converts sugar to acids, gases, or alcohol. It occurs in yeast and bacteria, and also in oxygen-starved muscle cells, Fermentation is also used more broadly to refer to the bulk growth of microorganisms on a growth medium, often with the goal of producing a specific chemical product. French microbiologist Louis Pasteur is often remembered for his insights into fermentation, the science of fermentation is known as zymology. Fermentation takes place when the transport chain is unusable. In this case it becomes the primary means of ATP production. Fermentation turns NADH and pyruvate produced in glycolysis into NAD+. In the presence of O2, NADH and pyruvate are used to generate ATP in respiration and this is called oxidative phosphorylation, and it generates much more ATP than glycolysis alone. For that reason, cells generally benefit from avoiding fermentation when oxygen is available, the exception being obligate anaerobes which cannot tolerate oxygen. The first step, glycolysis, is common to all fermentation pathways, two ADP molecules and two Pi are converted to two ATP and two water molecules via substrate-level phosphorylation. Two molecules of NAD+ are also reduced to NADH, in oxidative phosphorylation the energy for ATP formation is derived from an electrochemical proton gradient generated across the inner mitochondrial membrane via the electron transport chain. Humans have used fermentation to produce drinks and beverages since the Neolithic age, Fermentation can even occur within the stomachs of animals, such as humans. To many people, fermentation simply means the production of alcohol, grains and fruits are fermented to produce beer, if a food soured, one might say it was off or fermented. Here are some definitions of fermentation and they range from informal, general usage to more scientific definitions. Preservation methods for food via microorganisms, any process that produces alcoholic beverages or acidic dairy products. Any large-scale microbial process occurring with or without air, any energy-releasing metabolic process that takes place only under anaerobic conditions. Fermentation does not necessarily have to be carried out in an anaerobic environment, for example, even in the presence of abundant oxygen, yeast cells greatly prefer fermentation to aerobic respiration, as long as sugars are readily available for consumption. The antibiotic activity of hops also inhibits aerobic metabolism in yeast, Fermentation reacts NADH with an endogenous, organic electron acceptor. Usually this is formed from the sugar during the glycolysis step. Sugars are the most common substrate of fermentation, and typical examples of products are ethanol, lactic acid, carbon dioxide
18.
Gluconeogenesis
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Gluconeogenesis is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. From breakdown of proteins, these substrates include glucogenic amino acids, from breakdown of lipids, they include glycerol, gluconeogenesis is one of several main mechanisms used by humans and many other animals to maintain blood glucose levels, avoiding low levels. Other means include the degradation of glycogen, fatty acid breakdown, gluconeogenesis is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis takes place mainly in the liver and, to a lesser extent, in ruminants, this tends to be a continuous process. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, the process is highly endergonic until it is coupled to the hydrolysis of ATP or GTP, effectively making the process exergonic. For example, the leading from pyruvate to glucose-6-phosphate requires 4 molecules of ATP and 2 molecules of GTP to proceed spontaneously. Gluconeogenesis is often associated with ketosis, gluconeogenesis is also a target of therapy for type 2 diabetes, such as the antidiabetic drug, metformin, which inhibits glucose formation and stimulates glucose uptake by cells. In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, in humans the main gluconeogenic precursors are lactate, glycerol, alanine and glutamine. Altogether, they account for over 90% of the overall gluconeogenesis, other glucogenic amino acids as well as all citric acid cycle intermediates, the latter through conversion to oxaloacetate, can also function as substrates for gluconeogenesis. In ruminants, propionate is the principal gluconeogenic substrate, lactate is transported back to the liver where it is converted into pyruvate by the Cori cycle using the enzyme lactate dehydrogenase. Pyruvate, the first designated substrate of the pathway, can then be used to generate glucose. Transamination or deamination of amino acids facilitates entering of their carbon skeleton into the cycle directly, whether even-chain fatty acids can be converted into glucose in animals has been a longstanding question in biochemistry. It is known that odd-chain fatty acids can be oxidized to yield propionyl-CoA, a precursor for succinyl-CoA, in plants, specifically seedlings, the glyoxylate cycle can be used to convert fatty acids into the primary carbon source of the organism. The glyoxylate cycle produces four-carbon dicarboxylic acids that can enter gluconeogenesis, in 1995, researchers identified the glyoxylate cycle in nematodes. In addition, the glyoxylate enzymes malate synthase and isocitrate lyase have been found in animal tissues, genes coding for malate synthase have been identified in other metazoans including arthropods, echinoderms, and even some vertebrates. Mammals found to possess these genes include monotremes and marsupials but not placental mammals, genes for isocitrate lyase are found only in nematodes, in which, it is apparent, they originated in horizontal gene transfer from bacteria. The existence of cycles in humans has not been established. However, carbon-14 has been shown to end up in glucose when it is supplied in fatty acids
19.
Glycogenesis
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Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage. Glucose is converted into glucose-6-phosphate by the action of glucokinase or hexokinase, glucose-6-phosphate is converted into glucose-1-phosphate by the action of phosphoglucomutase, passing through the obligatory intermediate glucose-1, 6-bisphosphate. Glucose-1-phosphate is converted into UDP-glucose by the action of the enzyme UDP-glucose pyrophosphorylase, pyrophosphate is formed, which is later hydrolysed by pyrophosphatase into two phosphate molecules. Glycogenin, a homodimer, has a residue on each subunit that serves as the anchor for the reducing end of glycogen. Initially, about eight UDP-glucose molecules are added to each tyrosine residue by glycogenin, one of the main forms of control is the varied phosphorylation of glycogen synthase and glycogen phosphorylase. This is regulated by enzymes under the control of hormonal activity, as such, there are many different possible effectors when compared to allosteric systems of regulation. Glycogen phosphorylase is activated by phosphorylation, whereas glycogen synthase is inhibited, Glycogen phosphorylase is converted from its less active b form to an active a form by the enzyme phosphorylase kinase. This latter enzyme is activated by protein kinase A and deactivated by phosphoprotein phosphatase-1. Protein kinase A itself is activated by the hormone adrenaline, epinephrine binds to a receptor protein that activates adenylate cyclase. Returning to glycogen phosphorylase, the less active b form can itself be activated without the conformational change, 5AMP acts as an allosteric activator, whereas ATP is an inhibitor, as already seen with phosphofructokinase control, helping to change the rate of flux in response to energy demand. Epinephrine not only activates glycogen phosphorylase but also inhibits glycogen synthase and this amplifies the effect of activating glycogen phosphorylase. This inhibition is achieved by a mechanism, as protein kinase A acts to phosphorylate the enzyme. This is known as reciprocal control. Refer to glycolysis for further information of the regulation of glycogenesis, insulin has an antagonistic effect to epinephrine signaling via the beta-adrenergic receptor. When insulin binds to its receptor, it results in the activation of Akt which in turn activates Phosphodiesterase, calcium ions or cyclic AMP act as secondary messengers. This is an example of negative control, the calcium ions activate phosphorylase kinase. This activates glycogen phosphorylase and inhibits glycogen synthase, glycogenolysis Glycogen synthase Glycogen storage disease
20.
Metabolism
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Metabolism is the set of life-sustaining chemical transformations within the cells of living organisms. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, usually, breaking down releases energy and building up consumes energy. The chemical reactions of metabolism are organized into metabolic pathways, in one chemical is transformed through a series of steps into another chemical. Enzymes act as catalysts that allow the reactions to proceed more rapidly, enzymes also allow the regulation of metabolic pathways in response to changes in the cells environment or to signals from other cells. The metabolic system of a particular organism determines which substances it will find nutritious, for example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals. The speed of metabolism, the rate, influences how much food an organism will require. A striking feature of metabolism is the similarity of the metabolic pathways. These striking similarities in metabolic pathways are likely due to their appearance in evolutionary history. Most of the structures that make up animals, plants and microbes are made from three classes of molecule, amino acids, carbohydrates and lipids. These biochemicals can be joined together to make such as DNA and proteins. Proteins are made of amino acids arranged in a linear chain joined together by peptide bonds, many proteins are enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical functions, such as those that form the cytoskeleton, Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes, and the cell cycle. Lipids are the most diverse group of biochemicals and their main structural uses are as part of biological membranes both internal and external, such as the cell membrane, or as a source of energy. Lipids are usually defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as benzene or chloroform, the fats are a large group of compounds that contain fatty acids and glycerol, a glycerol molecule attached to three fatty acid esters is called a triacylglyceride. Several variations on this structure exist, including alternate backbones such as sphingosine in the sphingolipids. Steroids such as cholesterol are another class of lipids. Carbohydrates are aldehydes or ketones, with hydroxyl groups attached. Carbohydrates are the most abundant biological molecules, and fill numerous roles, such as the storage and transport of energy, the basic carbohydrate units are called monosaccharides and include galactose, fructose, and most importantly glucose
21.
Fasting
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Fasting is a willing abstinence or reduction from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a period, usually a period of 24 hours. Water fasting allows drinking water but nothing else, other fasts may be partially restrictive, limiting only particular foods or substances. A fast may also be intermittent in nature, Fasting practices may preclude intercourse and other activities as well as food. In a physiological context, fasting may refer to the status of a person who has not eaten overnight. Several metabolic adjustments occur during fasting, and some tests are used to determine a fasting state. For example, a person is assumed to be fasting after 8–12 hours from their last meal, metabolic changes toward the fasting state begin after absorption of a meal, post-absorptive state is synonymous with this usage, in contrast to the postprandial state of ongoing digestion. A diagnostic fast refers to prolonged fasting conducted under observation for investigation of a problem, many people may also fast as part of a medical procedure or check-up such as a colonoscopy. Fasting is also a part of religious observances. Fasting is often practiced prior to surgery or other procedures that require general anesthetics because of the risk of aspiration of gastric contents after induction of anesthesia. Additionally, certain tests, such as cholesterol testing or certain blood glucose measurements require fasting for several hours so that a baseline can be established. In the case of a panel, failure to fast for a full 12 hours will guarantee an elevated triglyceride measurement. Fasting is of no help in preventing or treating cancer. Fasting can help alleviate symptoms of depression. However the psychological effects may include anxiety and depression. Fasting will lead to weight loss, using fasting for weight loss is considered dangerous. It has been argued that fasting makes one better appreciate food, Fasting is often used as a tool to make a political statement, to protest, or to bring awareness to a cause. A hunger strike is a method of non-violent resistance in which participants fast as an act of political protest, or to provoke feelings of guilt, a spiritual fast incorporates personal spiritual beliefs with the desire to express personal principles, sometimes in the context of a social injustice
22.
Cahill cycle
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The Cahill cycle, also known as the alanine cycle or glucose-alanine cycle, is the series of reactions in which amino groups and carbons from muscle are transported to the liver. It is quite similar to the Cori cycle in the cycling of nutrients between skeletal muscle and the liver, when muscles degrade amino acids for energy needs, the resulting nitrogen is transaminated to pyruvate to form alanine. This is performed by the enzyme alanine transaminase, which converts L-glutamate and pyruvate into α-ketoglutarate, the resulting L-alanine is shuttled to the liver where the nitrogen enters the urea cycle and the pyruvate is used to make glucose. The Cahill cycle is less productive than the Cori cycle, which uses lactate, removal of the urea is energy-dependent, requiring four high-energy phosphate bonds, thus the net ATP produced is less than that found in the Cori cycle. However, unlike in the Cori cycle, NADH is conserved because lactate is not formed and this allows for it to be oxidized via the electron transport chain. This pathway requires the presence of alanine aminotransferase, which is restricted to such as muscle, liver. The alanine cycle also serves other purposes, Recycles carbon skeletons between muscle and liver Transports ammonium to the liver and is converted into urea
23.
Wayback Machine
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The Internet Archive launched the Wayback Machine in October 2001. It was set up by Brewster Kahle and Bruce Gilliat, and is maintained with content from Alexa Internet, the service enables users to see archived versions of web pages across time, which the archive calls a three dimensional index. Since 1996, the Wayback Machine has been archiving cached pages of websites onto its large cluster of Linux nodes and it revisits sites every few weeks or months and archives a new version. Sites can also be captured on the fly by visitors who enter the sites URL into a search box, the intent is to capture and archive content that otherwise would be lost whenever a site is changed or closed down. The overall vision of the machines creators is to archive the entire Internet, the name Wayback Machine was chosen as a reference to the WABAC machine, a time-traveling device used by the characters Mr. Peabody and Sherman in The Rocky and Bullwinkle Show, an animated cartoon. These crawlers also respect the robots exclusion standard for websites whose owners opt for them not to appear in search results or be cached, to overcome inconsistencies in partially cached websites, Archive-It. Information had been kept on digital tape for five years, with Kahle occasionally allowing researchers, when the archive reached its fifth anniversary, it was unveiled and opened to the public in a ceremony at the University of California, Berkeley. Snapshots usually become more than six months after they are archived or, in some cases, even later. The frequency of snapshots is variable, so not all tracked website updates are recorded, Sometimes there are intervals of several weeks or years between snapshots. After August 2008 sites had to be listed on the Open Directory in order to be included. As of 2009, the Wayback Machine contained approximately three petabytes of data and was growing at a rate of 100 terabytes each month, the growth rate reported in 2003 was 12 terabytes/month, the data is stored on PetaBox rack systems manufactured by Capricorn Technologies. In 2009, the Internet Archive migrated its customized storage architecture to Sun Open Storage, in 2011 a new, improved version of the Wayback Machine, with an updated interface and fresher index of archived content, was made available for public testing. The index driving the classic Wayback Machine only has a bit of material past 2008. In January 2013, the company announced a ground-breaking milestone of 240 billion URLs, in October 2013, the company announced the Save a Page feature which allows any Internet user to archive the contents of a URL. This became a threat of abuse by the service for hosting malicious binaries, as of December 2014, the Wayback Machine contained almost nine petabytes of data and was growing at a rate of about 20 terabytes each week. Between October 2013 and March 2015 the websites global Alexa rank changed from 162 to 208, in a 2009 case, Netbula, LLC v. Chordiant Software Inc. defendant Chordiant filed a motion to compel Netbula to disable the robots. Netbula objected to the motion on the ground that defendants were asking to alter Netbulas website, in an October 2004 case, Telewizja Polska USA, Inc. v. Echostar Satellite, No.02 C3293,65 Fed. 673, a litigant attempted to use the Wayback Machine archives as a source of admissible evidence, Telewizja Polska is the provider of TVP Polonia and EchoStar operates the Dish Network
24.
PubMed Identifier
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PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
25.
Enzyme
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Enzymes /ˈɛnzaɪmz/ are macromolecular biological catalysts. Enzymes accelerate, or catalyze, chemical reactions, the molecules at the beginning of the process upon which enzymes may act are called substrates and the enzyme converts these into different molecules, called products. Almost all metabolic processes in the cell need enzymes in order to occur at rates fast enough to sustain life, the set of enzymes made in a cell determines which metabolic pathways occur in that cell. The study of enzymes is called enzymology, enzymes are known to catalyze more than 5,000 biochemical reaction types. Most enzymes are proteins, although a few are catalytic RNA molecules, enzymes specificity comes from their unique three-dimensional structures. Like all catalysts, enzymes increase the rate of a reaction by lowering its activation energy, some enzymes can make their conversion of substrate to product occur many millions of times faster. An extreme example is orotidine 5-phosphate decarboxylase, which allows a reaction that would take millions of years to occur in milliseconds. Chemically, enzymes are like any catalyst and are not consumed in chemical reactions, enzymes differ from most other catalysts by being much more specific. Enzyme activity can be affected by other molecules, inhibitors are molecules that decrease enzyme activity, many drugs and poisons are enzyme inhibitors. An enzymes activity decreases markedly outside its optimal temperature and pH, some enzymes are used commercially, for example, in the synthesis of antibiotics. French chemist Anselme Payen was the first to discover an enzyme, diastase and he wrote that alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells. In 1877, German physiologist Wilhelm Kühne first used the term enzyme, the word enzyme was used later to refer to nonliving substances such as pepsin, and the word ferment was used to refer to chemical activity produced by living organisms. Eduard Buchner submitted his first paper on the study of yeast extracts in 1897, in a series of experiments at the University of Berlin, he found that sugar was fermented by yeast extracts even when there were no living yeast cells in the mixture. He named the enzyme that brought about the fermentation of sucrose zymase, in 1907, he received the Nobel Prize in Chemistry for his discovery of cell-free fermentation. Following Buchners example, enzymes are usually named according to the reaction they carry out, the biochemical identity of enzymes was still unknown in the early 1900s. Sumner showed that the enzyme urease was a protein and crystallized it. These three scientists were awarded the 1946 Nobel Prize in Chemistry, the discovery that enzymes could be crystallized eventually allowed their structures to be solved by x-ray crystallography. This high-resolution structure of lysozyme marked the beginning of the field of structural biology, an enzymes name is often derived from its substrate or the chemical reaction it catalyzes, with the word ending in -ase
26.
Hexokinase
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A hexokinase is an enzyme that phosphorylates hexoses, forming hexose phosphate. In most organisms, glucose is the most important substrate of hexokinases, scientists have discovered and demonstrated that Hexokinase posses the ability to transfer a inorganic phosphate group from ATP to a substrate. Hexokinases should not be confused with glucokinase, which is an isoform of hexokinase. While other hexokinases are capable of phosphorylating several hexoses, glucokinase acts with a 50-fold lower substrate affinity and its only hexose substrate is glucose. Genes that encode hexokinase have been discovered in every domain of life, and exist among a variety of species range from bacteria, yeast. They are categorized as actin fold proteins, sharing a common ATP binding site core that is surrounded by more variable sequences which determine substrate affinities, several hexokinase isoforms or isozymes that provide different functions can occur in a single species. Phosphorylation of a such as glucose often limits it to a number of intracellular metabolic processes. This is because phosphorylated hexoses are charged, and thus difficult to transport out of a cell. Most bacterial hexokinases are approximately 50 kD in size, multicellular organisms including plants and animals often have more than one hexokinase isoform. Most are about 100 kD in size and consist of two halves, which share much sequence homology and this suggests an evolutionary origin by duplication and fusion of a 50kD ancestral hexokinase similar to those of bacteria. There are four important mammalian hexokinase isozymes that vary in subcellular locations and kinetics with respect to different substrates and conditions, and physiological function. They are designated hexokinases I, II, III, and IV or hexokinases A, B, C, and D. Hexokinases I, II, Hexokinases I and II follow Michaelis-Menten kinetics at physiologic concentrations of substrates. All three are strongly inhibited by their product, glucose-6-phosphate, molecular weights are around 100 kD. Each consists of two similar 50kD halves, but only in hexokinase II do both halves have functional active sites, Hexokinase I/A is found in all mammalian tissues, and is considered a housekeeping enzyme, unaffected by most physiological, hormonal, and metabolic changes. Hexokinase II/B constitutes the principal regulated isoform in many types and is increased in many cancers. It is the hexokinase found in muscle and heart, Hexokinase II is also located at the mitochondria outer membrane so it can have direct access to ATP. Hexokinase III/C is substrate-inhibited by glucose at physiologic concentrations, little is known about the regulatory characteristics of this isoform. Mammalian hexokinase IV, also referred to as glucokinase, differs from other hexokinases in kinetics, the location of the phosphorylation on a subcellular level occurs when glucokinase translocates between the cytoplasm and nucleus of liver cells
27.
HK1
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Hexokinase-1 is an enzyme that in humans is encoded by the HK1 gene on chromosome 10. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways and this gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with anemia due to hexokinase deficiency. Alternative splicing of this results in five transcript variants which encode different isoforms. Each isoform has a distinct N-terminus, the remainder of the protein is identical among all the isoforms, a sixth transcript variant has been described, but due to the presence of several stop codons, it is not thought to encode a protein. HK1 is one of four highly homologous hexokinase isoforms in mammalian cells, the HK1 gene spans approximately 131 kb and consists of 25 exons.85 kb downstream of exon R, is the first 5’ exon for the ubiquitously expressed HK1 isoform. Moreover, exon 7 encodes the porin-binding domain conserved in mammalian HK1 genes, meanwhile, the remaining 17 exons are shared among all HK1 isoforms. In addition to exon R, a stretch of the promoter that contains a GATA element, an SP1 site, CCAAT. This gene encodes a 100 kDa homodimer with a regulatory N-terminal domain, catalytic C-terminal domain, both terminal domains are composed of a large subdomain and a small subdomain. The flexible region of the C-terminal large subdomain can adopt various positions and is proposed to interact with the base of ATP, moreover, glucose and G6P bind in close proximity at the N- and C-terminal domains and stabilize a common conformational state of the C-terminal domain. A second model posits that G6P acts as an inhibitor that stabilizes the closed conformation. Results from several studies suggest that the C-terminal is capable of catalytic and regulatory action. Physiological levels of G6P can regulate this process by inhibiting HK1 as negative feedback, however, unlike HK2 and HK3, HK1 itself is not directly regulated by Pi, which better suits its ubiquitous catabolic role. By phosphorylating glucose, HK1 effectively prevents glucose from leaving the cell and, thus, specifically, OMM-bound HK1 binds VDAC1 to trigger opening of the mitochondrial permeability transition pore and release mitochondrial ATP to further fuel the glycolytic process. Another critical function for OMM-bound HK1 is cell survival and protection against oxidative damage, furthermore, HK1 has demonstrated anti-apoptotic activity by antagonizing Bcl-2 proteins located at the OMM, which then inhibits TNF-induced apoptosis. It is also expressed in cells derived from stem cells, such as RBCs, leukocytes. In rats, it is also the predominant hexokinase in fetal tissues, mutations in this gene are associated with type 4H of Charcot–Marie–Tooth disease, also known as Russe-type hereditary motor and sensory neuropathy. Due to the role of HK1 in glycolysis, hexokinase deficiency has been identified as a cause of erythroenzymopathies associated with hereditary non-spherocytic hemolytic anemia
28.
HK2
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Hexokinase 2 also known as HK2 is an enzyme which in humans is encoded by the HK2 gene on chromosome 2. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways and this gene encodes hexokinase 2, the predominant form found in skeletal muscle. It localizes to the membrane of mitochondria. Expression of this gene is insulin-responsive, and studies in rat suggest that it is involved in the rate of glycolysis seen in rapidly growing cancer cells. HK2 is one of four highly homologous hexokinase isoforms in mammalian cells, the HK2 gene spans approximately 50 kb and consists of 18 exons. There is also an HK2 pseudogene integrated into a long interspersed nuclear repetitive DNA element located on the X chromosome, though its DNA sequence is similar to the cDNA product of the actual HK2 mRNA transcript, it lacks an open reading frame for gene expression. This gene encodes a 100-kDa, 917-residue enzyme with highly similar N- and this high similarity, along with the existence of a 50-kDa hexokinase, suggests that the 100-kDa hexokinases originated from a 50-kDa precursor via gene duplication and tandem ligation. Despite there being two binding sites for glucose, it is proposed that glucose binding at one site induces a change which prevents a second glucose from binding the other site. Meanwhile, the first 12 amino acids of the highly hydrophobic N-terminal serve to bind the enzyme to the mitochondria, physiological levels of G6P can regulate this process by inhibiting HK2 as negative feedback, though inorganic phosphate can relieve G6P inhibition. Pi can also directly regulate HK2, and the double regulation may better suit its anabolic functions, by phosphorylating glucose, HK2 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism. Specifically, HK2 binds VDAC to trigger opening of the channel, another critical function for OMM-bound HK2 is mediation of cell survival. Activation of Akt kinase maintains HK2-VDAC coupling, which subsequently prevents cytochrome c release and apoptosis, one model proposes that HK2 competes with the pro-apoptotic proteins BAX to bind VDAC, and in the absence of HK2, BAX induces cytochrome c release. In fact, there is evidence that HK2 restricts BAX and BAK oligomerization, in a similar mechanism, the pro-apoptotic creatine kinase binds and opens VDAC in the absence of HK2. An alternative model proposes the opposite, that HK2 regulates binding of the anti-apoptotic protein Bcl-Xl to VDAC, in particular, HK2 is ubiquitously expressed in tissues, though it is majorly found in muscle and adipose tissue. In cardiac and skeletal muscle, HK2 can be bound to both the mitochondrial and sarcoplasmic membrane. HK2 gene expression is regulated by a phosphatidylinositol 3-kinaselp70 S6 protein kinase-dependent pathway and can be induced by such as insulin, hypoxia, cold temperatures. Its inducible expression indicates its adaptive role in responses to changes in the cellular environment. HK2 is highly expressed in cancers, including breast cancer
29.
HK3
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Hexokinase 3 also known as HK3 is an enzyme which in humans is encoded by the HK2 gene on chromosome 5. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways, similar to hexokinases 1 and 2, this allosteric enzyme is inhibited by its product glucose-6-phosphate. HK3 is one of four highly homologous hexokinase isoforms in mammalian cells and this protein has a molecular weight of 100 kDa and is composed of two highly similar 50-kDa domains at its N- and C-terminals. This high similarity, along with the and the existence of a 50-kDa hexokinase, suggests that the 100-kDa hexokinases originated from a 50-kDa precursor via gene duplication, moreover, the catalytic activity depends on the interaction between the two terminal domains. Unlike HK1 and HK2, HK3 lacks a mitochondrial binding sequence at its N-terminal, physiological levels of G6P can regulate this process by inhibiting HK3 as negative feedback, though inorganic phosphate can relieve G6P inhibition. Inorganic phosphate can also directly regulate HK3, and the double regulation may better suit its anabolic functions, by phosphorylating glucose, HK3 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism. Compared to HK1 and HK2, HK3 possesses an affinity for glucose and will bind the substrate even at physiological levels. Uniquely, HK3 can be inhibited by glucose at high concentrations, HK3 is also less sensitive to G6P inhibition. Despite its lack of association, HK3 also functions to protect the cell against apoptosis. Overall, HK3 may promote cell survival by controlling ROS levels, currently, only hypoxia is known to induce HK3 expression through a HIF-dependent pathway. The inducible expression of HK3 indicates its adaptive role in responses to changes in the cellular environment. In particular, HK3 is ubiquitously expressed in tissues, albeit at low abundance. Higher abundance levels have been cited in lung, kidney, within cells, HK3 localizes to the cytoplasm and putatively binds the perinuclear envelope. HK3 is the predominant hexokinase in myeloid cells, particularly granulocytes, HK3 is found to be overexpressed in malignant follicular thyroid nodules. In conjunction with cyclin A and galectin-3, HK3 could be used as biomarker to screen for malignancy in patients. Meanwhile, HK3 was found to be repressed in acute myeloid leukemia blast cells, regulators repressing HK3 expression in AML include PML-RARA and CEBPA. Regarding acute lymphoblastic leukemia, functional enrichment analysis revealed HK3 as a key gene and suggests that HK3 shares antiapoptotic function with HK1, the HK3 promoter is known to interact with PU.1, PML-RARA, and CEBPA. Click on genes, proteins and metabolites below to link to respective articles, hexokinase HK1 HK2 Glucokinase This article incorporates text from the United States National Library of Medicine, which is in the public domain
30.
Glucokinase
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Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans, mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia. Glucokinase is a hexokinase isozyme, related homologously to at least three other hexokinases, all of the hexokinases can mediate phosphorylation of glucose to glucose-6-phosphate, which is the first step of both glycogen synthesis and glycolysis. However, glucokinase is coded by a gene and its distinctive kinetic properties allow it to serve a different set of functions. Because of this reduced affinity, the activity of glucokinase, under physiological conditions. Alternative names for this enzyme are, human hexokinase IV, hexokinase D, the common name, glucokinase, is derived from its relative specificity for glucose under physiologic conditions.7.1.2. Nevertheless, glucokinase remains the name preferred in the contexts of medicine, another mammalian glucose kinase, ADP-specific glucokinase, was discovered in 2004. The gene is distinct and similar to that of primitive organisms and it is dependent on ADP rather than ATP, and the metabolic role and importance remain to be elucidated. The principal substrate of physiologic importance of glucokinase is glucose, the other necessary substrate, from which the phosphate is derived, is adenosine triphosphate, which is converted to adenosine diphosphate when the phosphate is removed. The reaction catalyzed by glucokinase is, ATP participates in the reaction in a form complexed to magnesium as a cofactor, furthermore, under certain conditions, glucokinase, like other hexokinases, can induce phosphorylation of other hexoses and similar molecules. Two important kinetic properties distinguish glucokinase from the other hexokinases, allowing it to function in a role as glucose sensor. Glucokinase has an affinity for glucose than the other hexokinases. Glucokinase changes conformation and/or function in parallel with rising glucose concentrations in the physiologically important range of 4–10 mmol/L and it is half-saturated at a glucose concentration of about 8 mmol/L. Glucokinase is not inhibited by its product, glucose-6-phosphate and this allows continued signal output amid significant amounts of its product These two features allow it to regulate a supply-driven metabolic pathway. That is, the rate of reaction is driven by the supply of glucose, another distinctive property of glucokinase is its moderate cooperativity with glucose, with a Hill coefficient of about 1.7. Glucokinase has only a binding site for glucose and is the only monomeric regulatory enzyme known to display substrate cooperativity. The nature of the cooperativity has been postulated to involve a transition between two different enzyme states with different rates of activity. If the dominant state depends upon glucose concentration, it would produce an apparent cooperativity similar to that observed, because of this cooperativity, the kinetic interaction of glucokinase with glucose does not follow classical Michaelis-Menten kinetics
31.
Glucose 6-phosphatase
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Glucose 6-phosphatase is an enzyme that hydrolyzes glucose-6-phosphate, resulting in the creation of a phosphate group and free glucose. Glucose is then exported from the cell via glucose transporter membrane proteins and this catalysis completes the final step in gluconeogenesis and glycogenolysis and therefore plays a key role in the homeostatic regulation of blood glucose levels. Glucose-6-phosphatase is a complex of multiple component proteins, including transporters for G6P, glucose, the main phosphatase function is performed by the glucose-6-phosphatase catalytic subunit. In humans, there are three isozymes of the subunit, glucose-6-phosphatase-α, encoded by G6PC, IGRP, encoded by G6PC2. In contrast, IGRP has almost no activity, and may play a different role in stimulating pancreatic insulin secretion. Although a clear consensus has not been reached, a number of scientists adhere to a substrate-transport model to account for the catalytic properties of glucose-6-phosphatase. In this model, glucose-6-phosphatase has a low degree of selectivity, the transfer of the glucose 6-phosphate is carried out by a transporter protein and the endoplasmic reticulum contains structures allowing the exit of the phosphate group and glucose. Glucose-6-phosphatase consists of 357 amino acids, and is anchored to the endoplasmic reticulum by nine transmembrane helicies and its N-terminal and active site are found on the lumen side of the ER and its C-terminus projects into the cytoplasm. Due to its association to the ER, the exact structure of glucose-6-phosphatase remains unknown. However, sequence alignment has shown that glucose-6-phosphatase is structurally similar to the site of the vanadium-containing chloroperoxidase found in Curvularia inaequalis. Essential residues in the site of vanadium haloperoxidases include, Lys353, Arg360, Arg490, His404. Within the Vanadium-containing chloroperoxidase, Lys353 was found to stabilize the phosphate in the transition state, however, the corresponding residue in glucose-6-phosphatase-α resides within the ER membrane and its function, if any, is currently undetermined. With the exception of Lys76, these residues are all located on the side of the ER membrane. Glucose-6-phosphatase-β is a ubiquitously expressed, 346-amino acid membrane protein that shares 36% sequence identity with glucose-6-phosphatase-α, within the glucose-6-phosphatase-β enzyme, sequence alignments predict that its active site contains His167, His114, and Arg79. Similar to that of the active site, His167 is the residue that provides the nucleophilic attack, and His114. Glucose-6-phosphatase-β is also localized in the ER membrane, although its orientation is unknown, the hydrolysis of glucose-6-phosphate begins with a nucleophilic attack on the sugar-bound phosphate by His176 resulting in the formation of a phosphohistidine bond and the degradation of a carbonyl. A Negatively charged oxygen then transfers its electrons reforming a carbonyl, the negatively charged glucose-bound oxygen is then protonated by His119 forming a free glucose. Genes coding for the enzyme are primarily expressed in the liver, in the cortex and in the β-cells of the pancreatic islets
32.
Glucose-6-phosphate isomerase
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Glucose-6-phosphate isomerase, alternatively known as phosphoglucose isomerase or phosphohexose isomerase, is an enzyme that in humans is encoded by the GPI gene on chromosome 19. This gene encodes a member of the glucose phosphate isomerase protein family, the encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as an enzyme that interconverts glucose-6-phosphate and fructose-6-phosphate. The encoded protein is referred to as autocrine motility factor based on an additional function as a tumor-secreted cytokine. Defects in this gene are the cause of hemolytic anemia. Alternative splicing results in transcript variants. Functional GPI is a 64-kDa dimer composed of two identical monomers, the two monomers interact notably through the two protrusions in a hugging embrace. The active site of each monomer is formed by a cleft between the two domains and the dimer interface, GPI monomers are made of two domains, one made of two separate segments called the large domain and the other made of the segment in between called the small domain. The two domains are each αβα sandwiches, with the small domain containing a five-strand β-sheet surrounded by α-helices while the domain has a six-stranded β-sheet. The large domain, located at the N-terminal, and the C-terminal of each monomer also contain arm-like protrusions, since the isomerization activity occurs at the dimer interface, the dimer structure of this enzyme is critical to its catalytic function. It is hypothesized that serine phosphorylation of this protein induces a change to its secretory form. Compound C00668 at KEGG Pathway Database, enzyme 5.3.1.9 at KEGG Pathway Database. Compound C05345 at KEGG Pathway Database, reaction R00771 at KEGG Pathway Database. Glucose 6-phosphate binds to GPI in its pyranose form, the ring is opened in a push-pull mechanism by His388, which protonates the C5 oxygen, and Lys518, which deprotonates the C1 hydroxyl group. This creates an open chain aldose, then, the substrate is rotated about the C3-C4 bond to position it for isomerization. At this point, Glu357 deprotonates C2 to create a cis-enediolate intermediate stabilized by Arg272, to complete the isomerization, Glu357 donates its proton to C1, the C2 hydroxyl group loses its proton and the open-chain ketose fructose 6-phosphate is formed. Finally, the ring is closed by rotating the substrate about the C3-C4 bond again and this gene belongs to the GPI family. The protein encoded by this gene is an enzyme that catalyzes the reversible isomerization of G6P and F6P
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Phosphofructokinase 1
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Phosphofructokinase-1 is one of the most important regulatory enzymes of glycolysis. It is an enzyme made of 4 subunits and controlled by many activators and inhibitors. PFK-1 catalyzes the important committed step of glycolysis, the conversion of fructose 6-phosphate and ATP to fructose 1, 6-bisphosphate, glycolysis is the foundation for respiration, both anaerobic and aerobic. PFK is able to regulate glycolysis through allosteric inhibition, and in this way, for example, a high ratio of ATP to ADP will inhibit PFK and glycolysis. The key difference between the regulation of PFK in eukaryotes and prokaryotes is that in eukaryotes PFK is activated by fructose 2, the purpose of fructose 2, 6-bisphosphate is to supersede ATP inhibition, thus allowing eukaryotes to have greater sensitivity to regulation by hormones like glucagon and insulin. Mammalian PFK1 is a 340kd tetramer composed of different combinations of three types of subunits, muscle, liver, and platelet, the composition of the PFK1 tetramer differs according to the tissue type it is present in. For example, mature muscle expresses only the M isozyme, therefore, the liver and kidneys express predominantly the L isoform. In erythrocytes, both M and L subunits randomly tetramerize to form M4, L4 and the three forms of the enzyme. As a result, the kinetic and regulatory properties of the various isoenzymes pools are dependent on subunit composition, tissue-specific changes in PFK activity and isoenzymic content contribute significantly to the diversities of glycolytic and gluconeogenic rates which have been observed for different tissues. PFK1 is an enzyme and has a structure similar to that of hemoglobin in so far as it is a dimer of a dimer. One half of each contains the ATP binding site whereas the other half the substrate binding site as well as a separate allosteric binding site. Each subunit of the tetramer is 319 amino acids and consists of two domain, one that binds the substrate ATP, and the other that binds fructose-6-phosphate, each domain is a b barrel, and has cylindrical b sheet surrounded by alpha helices. On the opposite side of the each subunit from each site is the allosteric site. ATP and AMP compete for this site, F6P binds with a high affinity to the R state but not the T state enzyme. For every molecule of F6P that binds to PFK1, the enzyme progressively shifts from T state to the R state, thus a graph plotting PFK1 activity against increasing F6P concentrations would adopt the sigmoidal curve shape traditionally associated with allosteric enzymes. PFK1 belongs to the family of phosphotransferases and it catalyzes the transfer of γ-phosphate from ATP to fructose-6-phosphate, the PFK1 active site comprises both the ATP-Mg2+ and the F6P binding sites. Some proposed residues involved with substrate binding in E. coli PFK1 include Asp127, in the T state, enzyme conformation shifts slightly such that the space previously taken up by the Arg162 is replaced with Glu161. This swap in positions between adjacent amino acid residues inhibits the ability of F6P to bind the enzyme, allosteric activators such as AMP and ADP bind to the allosteric site as to facilitate the formation of the R state by inducing structural changes in the enzyme
34.
PFKM
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6-phosphofructokinase, muscle type is an enzyme that in humans is encoded by the PFKM gene on chromosome 12. Three phosphofructokinase isozymes exist in humans, muscle, liver and platelet and these isozymes function as subunits of the mammalian tetramer phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1, 6-bisphosphate. Tetramer composition varies depending on tissue type and this gene encodes the muscle-type isozyme. Mutations in this gene have been associated with glycogen storage disease type VII, alternatively spliced transcript variants have been described. This gene is found on chromosome 12, the coding region in PFKM only shares a 68% similarity with that of the liver-type PFKL. This 85-kDa protein is one of two types that comprise the seven tetrameric PFK isozymes. The muscle isozyme is composed solely of PFKM, the liver PFK contains solely the second subunit type, PFKL, while the erythrocyte PFK includes five isozymes composed of different combinations of PFKM and PFKL. These subunits evolved from a common ancestor via gene duplication and mutation events. Generally, the N-terminal of the subunits carries out their catalytic activity while the C-terminal contains allosteric ligand binding sites, in particular, the binding site for the PFK inhibitor citrate is found in the PFKL C-terminal region. This gene encodes one of three subunits of PFK, which are expressed and combined to form the tetrameric PFK in a tissue-specific manner. As a PFK subunit, PFKL is involved in catalyzing the phosphorylation of fructose 6-phosphate to fructose 1 and this irreversible reaction serves as the major rate-limiting step of glycolysis. Though the PFKM subunit majorly incorporates into muscle and erythrocyte PFKs, PFKM also is expressed in the heart, brain, notably, mutations in PFKM have been shown to cause Tarui disease due to homozygosity for catalytically inactive M subunits. PFKM is confirmed to be involved in muscle PFK deficiency with early-onset hyperuricemia, interestingly, even though PFKM functions to drive glycolysis, its overexpression has been associated with type 2 diabetes and insulin resistance in skeletal muscle. PFKM has been shown to interact with ATP6V0A4, click on genes, proteins and metabolites below to link to respective articles
35.
PFKP
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Phosphofructokinase, platelet, also known as PFKP is an enzyme which in humans is encoded by the PFKP gene. The PFKP gene encodes the platelet isoform of phosphofructokinase, PFK catalyzes the irreversible conversion of fructose 6-phosphate to fructose 1, 6-bisphosphate and is a key regulatory enzyme in glycolysis. The PFKP gene, which maps to chromosome 10p, is expressed in fibroblasts. See also the muscle and liver isoforms of phosphofructokinase, which map to chromosomes 12q13 and 21q22, full tetrameric phosphofructokinase enzyme expressed in platelets can be composed of subunits P4, P3L, and P2L2. Click on genes, proteins and metabolites below to link to respective articles and this article incorporates text from the United States National Library of Medicine, which is in the public domain
36.
Fructose 1,6-bisphosphatase
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Fructose bisphosphatase is an enzyme that converts fructose-1, 6-bisphosphate to fructose 6-phosphate in gluconeogenesis and the Calvin cycle which are both anabolic pathways. Fructose bisphosphatase catalyses the reverse of the reaction which is catalysed by phosphofructokinase in glycolysis, more specifically, fructose 2, 6-bisphosphate allosterically inhibits fructose 1, 6-bisphosphatase, but activates phosphofructokinase-I. Fructose 1, 6-bisphosphatase is involved in many different metabolic pathways, FBPase requires metal ions for catalysis and the enzyme is potently inhibited by Li+. The fold of fructose-1, 6-bisphosphatase from pig was noted to be identical to that of inositol-1-phosphatase, inositol polyphosphate 1-phosphatase, IMPase and FBPase share a sequence motif which has been shown to bind metal ions and participate in catalysis. This motif is found in the distantly-related fungal, bacterial. Three different groups of FBPases have been identified in eukaryotes and bacteria, none of these groups have been found in archaea so far, though a new group of FBPases which also show inositol monophosphatase activity has recently been identified in archaea. A new group of FBPases is found in archaea and the hyperthermophilic bacterium Aquifex aeolicus. The characterised members of this group show strict substrate specificity for FBP and are suggested to be the true FBPase in these organisms, the arrangement of the catalytic side chains and metal ligands was found to be consistent with the three-metal ion assisted catalysis mechanism proposed for other FBPases. The fructose 1, 6-bisphosphatases found within the Firmicutes do not show any significant sequence similarity to the enzymes from other organisms, the Bacillus subtilis enzyme is inhibited by AMP, though this can be overcome by phosphoenolpyruvate, and is dependent on Mn. Mutants lacking this enzyme are still able to grow on gluconeogenic growth substrates such as malate. Click on genes, proteins and metabolites below to link to respective articles, during hibernation, an animal’s metabolic rate may decrease to around 1/25 of its euthermic resting metabolic rate. Studies have found that FBPase is modified in hibernating animals to be much more sensitive than it is in euthermic animals. In one study, FBPase in the liver of a hibernating bat showed a 75% decrease in Km for its substrate FBP at 5°C than at 37°C, however, in a euthermic bat this decrease was only 25%, demonstrating the difference in temperature sensitivity between hibernating and euthermic bats. During hibernation, respiration also dramatically decreases, resulting in conditions of relative anoxia in the tissues, anoxic conditions inhibit gluconeogenesis, and therefore FBPase, while stimulating glycolysis, and this is another reason for reduced FBPase activity in hibernating animals. In addition to hibernation, there is evidence that FBPase activity varies significantly between warm and cold even for animals that do not hibernate. In rabbits exposed to temperatures, FBPase activity decreased throughout the duration of cold exposure. The mechanism of this FBPase inhibition is thought to be digestion of FBPase by lysosomal proteases, inhibition of FBPase through proteolytic digestion decreases gluconeogenesis relative to glycolysis during cold periods, similar to hibernation. Fructose 1, 6-bisphosphate aldolase is another temperature dependent enzyme that plays an important role in the regulation of glycolysis and gluconeogenesis during hibernation
37.
Fructose-bisphosphate aldolase
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Aldolase can also produce DHAP from other -ketose 1-phosphates such as fructose 1-phosphate and sedoheptulose 1, 7-bisphosphate. Gluconeogenesis and the Calvin cycle, which are anabolic pathways, use the reverse reaction, glycolysis, a catabolic pathway, uses the forward reaction. Aldolase is divided into two classes by mechanism, the word aldolase also refers, more generally, to an enzyme that performs an aldol reaction or its reverse, such as the one that forms sialic acid. Class I proteins form a protonated Schiff base intermediate linking a highly conserved active site lysine with the DHAP carbonyl carbon, additionally, tyrosine residues are crucial to this mechanism in acting as stabilizing hydrogen acceptors. Class II proteins use a different mechanism which polarizes the carbonyl group with a divalent cation like Zn2+, two histidine residues in the first half of the sequence of these homologs have been shown to be involved in binding zinc. The protein subunits of both classes each have an α/β domain folded into a TIM barrel containing the active site, several subunits are assembled into the complete protein. The two classes share little sequence identity, with few exceptions only class I proteins have been found in animals, plants, and green algae. With few exceptions only class II proteins have been found in fungi, both classes have been found widely in other eukaryotes and in bacteria. The two classes are present together in the same organism. Plants and algae have plastidal aldolase, sometimes a relic of endosymbiosis, a bifunctional fructose-bisphosphate aldolase/phosphatase, with class I mechanism, has been found widely in archaea and in some bacteria. The active site of this archaeal aldolase is also in a TIM barrel, gluconeogenesis and glycolysis share a series of six reversible reactions. In gluconeogenesis glyeraldehyde-3-phosphate is reduced to fructose 1, 6-bisphosphate with aldolase, in glycolysis fructose 1, 6-bisphosphate is made into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate through the use of aldolase. The aldolase used in gluconeogenesis and glycolysis is a cytoplasmic protein, three forms of class I protein are found in vertebrates. Aldolase A is preferentially expressed in muscle and brain, aldolase B in liver, kidney, and in enterocytes, aldolases A and C are mainly involved in glycolysis, while aldolase B is involved in both glycolysis and gluconeogenesis. Some defects in aldolase B cause hereditary fructose intolerance, the metabolism of free fructose in liver exploits the ability of aldolase B to use fructose 1-phosphate as a substrate. Archaeal fructose-bisphosphate aldolase/phosphatase is presumably involved in gluconeogenesis because its product is fructose 6-phosphate, the Calvin cycle is a carbon fixation pathway. It and gluconeogenesis share a series of four reversible reactions, in both pathways 3-phosphoglycerate is reduced to fructose 1, 6-bisphosphate with aldolase catalyzing the last reaction. A fifth reaction, catalyzed in both pathways by fructose 1, 6-bisphosphatase, hydrolyzes the fructose 1-6-bisphosphate to fructose 6-phosphate and inorganic phosphate, the large decrease in free energy makes this reaction irreversible
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